metformin associated lactic acidosis MALA

This patient’s history is most consistent with metformin-associated lactic acidosis (MALA). The patient has severe metabolic acidosis with very large anion gap, no osmolar gap (plasma osmolar gap calculation), and very increased serum lactate—that is, she has severe lactic acidosis. However, aside from the lactate level itself, there is no evidence of shock of any type, nor is there evidence of infection. Osmolar gap is normal, ruling out concomitant methanol or ethylene glycol ingestion. Ketones are not measured, but the delta anion gap:delta bicarbonate ratio is 1.95, most consistent with pure lactic acidosis.

MALA is an uncommon but potentially life-threatening complication of both chronic metformin use and acute overdose. The associated mortality is 30% to 50%. MALA is a form of type B lactic acidosis, not associated with tissue hypoxia (lactic acidosis types). The mechanism of lactic acidosis appears to be via its interaction with cytochrome complexes I and IV, resulting in impaired oxidative phosphorylation. Metformin toxicity tends to result in very high serum lactate levels, in comparison with type A lactic acidoses; one study demonstrated median lactate levels of 53.15 mg/dL (5.9 mmol/L) in septic shock, compared with median levels of 132.43 mg/dL (14.7 mmol/L) in MALA.

MALA is associated with a high mortality (30%-44%), and there is no antidote. The use of sodium bicarbonate infusion in MALA is controversial, as it is in other lactic acid-producing states. Its use should be limited to patients with severe metabolic acidosis as a bridge to recovery or extracorporeal treatment removal (ECTR). In 2015, the Extracorporeal Treatments in Poisoning Workgroup recommended ECTR in severe metformin poisoning defined as meeting any of the following criteria: (1) severely elevated serum lactate concentration (>135.14 mg/dL [15 mmol/L]), (2) severe metabolic acidosis (pH ≤7.0), (3) failure to improve with standard supportive care, or (4) presence of comorbid conditions (shock, impaired kidney function, hepatic failure, decreased level of consciousness). Intermittent hemodialysis (with bicarbonate buffer) is preferred, but continuous renal replacement therapies can be used if intermittent hemodialysis is unavailable.

Most patients with metformin toxicity do not require endotracheal intubation and invasive mechanical ventilation (IMV). Tachypnea and hyperpnea in patients with MALA typically reflect respiratory compensation for metabolic acidosis, as in this patient’s case (choice A is incorrect). Moreover, it can be difficult to match patients’ intrinsic respiratory compensation and minute ventilation in the peri-intubation time frame, which could lead to worsening acidemia and decompensation. If IMV is required for another indication, clinicians should be highly attuned to the risk of worsening acidemia, which can be mitigated by maximizing minute ventilation through the ventilator.123456

This patient has rapidly escalating shock and severe lactic acidosis. Although this could be due to fulminant septic shock, for which the patient is receiving evaluation and treatment, it is likely to be life-threatening metformin toxicity. Her symptoms developed during ongoing therapeutic metformin administration without dosing adjustment in the setting of new-onset renal failure. The symptoms of metformin toxicity are generally nonspecific—nausea, vomiting, abdominal pain, diarrhea, confusion, dyspnea, or a combination of these—and the diagnosis requires recognizing the connection of unexplained lactic acidosis to ingestion of metformin despite renal failure or metformin overdose. As in this case, lactate accumulation and hemodynamic deterioration can be rapid and, if untreated, often fatal.

The most effective treatment for this condition is hemodialysis (HD) or another extracorporeal technique (continuous renal replacement therapy [CRRT], hemoperfusion, or plasma exchange) and, given the propensity for rapid progression, should be initiated as quickly as possible (choice C is correct).

Hemodialysis is preferred over CRRT because it more effectively provides rapid clearance. The feasibility of performing HD during administration of high doses of vasopressors has been demonstrated in case series of severe metformin toxicity that generally showed progressive improvement in hemodynamic status as HD is performed. Some experts recommend hemodialysis for all metformin-toxic patients with severely elevated serum lactate >180.18 mg/dL (>20 mmol/L), severe metabolic acidosis (pH <7.0), and failure to improve with supportive care and bicarbonate therapy within 2 to 4 h. However, case series indicate metformin toxicity is nearly uniformly fatal if pH is <6.9 and lactate is >225.23 mg/dL (>25 mmol/L)—and acute dialysis may take time to initiate. Other experts advise slightly broader indications, including lactate of 135.14 to 180.18 mg/dL (15-20 mmol/L), pH of 7.0 to 7.1, or comorbidities (shock; acute kidney injury [serum creatinine >22.624 mg/dL (>2,000 μmol/L)] or chronic kidney disease; liver failure [international normalized ratio >1.5] or encephalopathy; or decreased level of consciousness). This patient meets these criteria. Although treatment with sodium bicarbonate infusion is controversial, some experts recommend administering it to keep pH >7.1. Hemodialysis should be performed with a bicarbonate buffer.

Metformin is the most commonly prescribed of the biguanides, which are oral antihyperglycemic agents that promote euglycemia via reducing intestinal absorption of glucose, decreasing gluconeogenesis, and increasing peripheral glucose utilization. It is excreted unchanged by the kidneys and accumulates in renal failure. Metformin typically does not result in hypoglycemia, and although frequent monitoring of glucose should be performed, initiation of dextrose 10% in water by rapid infusion is not indicated at this time for hypoglycemia or as a treatment for metformin toxicity (choice B is incorrect).

The angiotensin-converting enzyme inhibitor lisinopril is cleared by the kidney; in this patient, it likely has also accumulated in the presence of progressive renal failure, potentially contributing to her current toxic state. Lisinopril toxicity is characterized by hemodynamic instability, renal failure, and hyperkalemia. Treatment is generally supportive, but patients with hemodynamic instability and persistent toxicity may benefit from hemodialysis.

The patient was also taking the sustained-release β-blocker metoprolol succinate. This agent is metabolized by the hepatic CYP2D6 enzyme system and should not accumulate in the setting of renal failure with normal liver function. Although the patient has hypotension, there is no evidence of either bradycardia or cardiac conduction delays. Glucagon IV has been used for treatment of β-blocker poisoning but is not indicated in this case (choice A is incorrect).

Toxic alcohol ingestions, including from methanol or ethylene glycol ingestion, can produce high anion gap metabolic acidosis but also produce a high osmolal gap, which is not present in this patient. Treatment with fomepizole is not indicated (choice D is incorrect).

A 55-year-old woman with coronary artery disease, chronic systolic heart failure, and type 2 diabetes was briefly hospitalized several weeks ago for urinary tract infection and chest pain. At that time she received antibiotics and underwent cardiac catheterization, which revealed no change in coronary disease and patent coronary stents. She is now admitted to the hospital after having progressive reduction in urine output, nausea, diarrhea, weakness, and fatigue during the past week with accentuation in the past day, including vomiting and mild confusion. Medications she has continued to take despite nausea include atorvastatin, clopidogrel, lisinopril, metformin, and metoprolol succinate. She appears dehydrated and mildly confused and is afebrile.

Her vital signs are a heart rate of 80/min, a respiratory rate of 28/min, a BP of 85/45 mm Hg, and an SpO2 of 96% on room air. Initial laboratory findings are in Figure 1.

Results of urinalysis reveal mild proteinuria, and a few WBCs, RBCs, and bacteria are evident on microscopic examination. One set of cardiac enzymes is negative. Her chest radiography is clear. ECG reveals sinus rhythm, QTc 470 ms, and left ventricular hypertrophy (LVH). After blood and urine cultures are obtained, empiric broad IV antimicrobial therapy is begun. Medical management of hyperkalemia is started. Despite receiving 1.5 L of lactated Ringer’s solution and one ampoule of NaHCO3, she has progressive hypotension and requires escalating doses of norepinephrine by infusion. Limited bedside echocardiogram is largely unchanged from prior studies revealing mild LVH, reduced ejection fraction of 35% to 40%, and normal right heart function. The result of a repeat measurement of arterial lactate is now 150.45 mg/dL (16.7 mmol/L), and arterial blood gas levels are as follows: pH of 7.07, PCO2 of 15 mm Hg, PO2 of 120 mm Hg, and HCO3 of 6 mEq/L (6 mmol/L).

Which of the following interventions is indicated at this time?

Footnotes

  1. SEEK Questionnaires ↩

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  3. Di Magno L, Di Pastena F, Bordone R, Coni S, Canettieri G. The mechanism of action of biguanides: new answers to a complex question. Cancers (Basel). 2022;14(13):3220. PubMed ↩

  4. van Berlo-van de Laar IRF, Gedik A, van ‘t Riet E, de Meijer A, Taxis K, Jansman FGA. Identifying patients with metformin associated lactic acidosis in the emergency department. Int J Clin Pharm. 2020;42(5):1286-1292. PubMed ↩

  5. Calello DP, Liu KD, Wiegand TJ, et al; Extracorporeal Treatments in Poisoning Workgroup. Extracorporeal treatment for metformin poisoning: systematic review and recommendations from the Extracorporeal Treatments in Poisoning Workgroup. Crit Care Med. 2015;43(8):1716-1730. PubMed ↩

  6. Fenves AZ, Kirkpatrick HM 3rd, Patel VV, et al. Increased anion gap metabolic acidosis as a result of 5-oxoproline (pyroglutamic acid): a role for acetaminophen. Clin J Am Soc Nephrol. 2006;1(3):441-447. PubMed ↩